tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

While trastuzumab-based chemotherapy has shown remarkable clinical benefits for HER2-positive breast cancer patients, a subset of patients (30%–40%) shows little or no effect. This highlights an important clinical need for biomarkers in addition to HER2 for better stratification of patients for therapy. In this multicenter retrospective study by Kang and colleagues, patients with HER2-positive breast cancer that also overexpress WBP2 had better pathologic complete response to trastuzumab-based neoadjuvant therapy. The potential to predict which patients would attain successful downstaging of their tumors from neoadjuvant therapy could help guide surgical decisions; for example, breast-conserving surgery versus mastectomy, consequently improving patients' outcome.Extending previous studies in more restricted populations, Nassar and colleagues examined 472 patients across the spectrum of urothelial carcinoma from nonmuscle-invasive bladder cancer (NMIBC) to upper-tract urothelial carcinoma (UTUC) for mutations in 237 cancer genes. Low-grade NMIBC has a distinct mutation spectrum from invasive disease, suggesting that it is truly a separate pathologic entity unrelated to invasive disease in most instances. Other key findings include enrichment of KDM6A mutations in women with low-grade NMIBC compared to men and identification of a subtype of high-grade UTUC with mutations in FGFR3, EP300, and PIK3CA associated with poorer survival.Drug-resistance is a major obstacle for the effective treatment of patients with high-grade serous ovarian cancer (HGSOC), often resulting in the selection of an ineffective treatment course. Using PET imaging with the radiotracer (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG), Greenwood and colleagues showed decreased radiotracer uptake in chemotherapy-resistant A2780 tumors compared with parental drug-sensitive tumors, demonstrating the ability of [18F]FSPG to detect upregulated antioxidant pathways present in drug-resistant cancer. [18F]FSPG may, therefore, enable the identification of HGSOC patients who are refractory to standard-of-care, allowing the transferal of drug-resistant patients to alternative therapies and thereby improving outcomes in this disease.To understand the immunological nature of glioblastoma, Park and colleagues examined the expression of immune checkpoint inhibitory receptors in tumor-infiltrating CD8+ T cells from patients with primary glioblastoma and their differentiation status. In addition, they investigated the reinvigoration ability of tumor-infiltrating CD8+ T cells by ex vivo treatment with anti-PD-1 and anti-CTLA-4. They demonstrated that the differentiation status of tumor-infiltrating CD8+ T cells determines the reinvigoration ability. This study provides a rationale for developing optimal strategies for immune checkpoint inhibitor treatment in patients with glioblastoma.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2019)

Circular RNAs in Prostate CancerCircular RNAs (circRNA), a new class of noncoding RNA are generated from precursor mRNA primarily through back-splicing events and form a covalently closed loop that increases their stability.Chen and colleagues reported transcriptome-wide discovery of circRNAs in localized prostate cancer by performing ultra-deep, non-polyA RNA sequencing on 144 prostate cancers.They identified >76,000 distinct circRNAs, with an average expression of 7,000 per tumor.Moreover, the aberrant production of circRNAs was associated with tumor progression.Subsequent loss-of-function screening identified circRNAs essential for cell proliferation including circCSNK1G3 that was shown to interact with miR-181 to promote cell growth.Interestingly, 11% of circRNAs were essential for proliferation, whereas the majority of linear counterparts were not, highlighting the potential of circRNAs as therapeutic targets.Expert Commentary: These results decipher the transcriptional landscape of circRNAs in prostate cancers and thereby add to the diversity of the prostate cancer transcriptome.CircRNAs show promise as diagnostic/prognostic biomarkers and therapeutic targets in cancer.(Image courtesy of Wikimedia
SARS‐CoV‐2 humoral responses following booster BNT162b2 vaccination in patients with B‐cell malignancies
Authors: Evangelos Terpos, Despina Fotiou, Vangelis Karalis, Ioannis Ntanasis‐Stathopoulos, Aimilia D. Sklirou, Maria Gavriatopoulou, Panagiotis Malandrakis, Vassiliki A. Iconomidou, Efstathios Kastritis, Ioannis P. Trougakos, Meletios A. Dimopoulos
Journal: American Journal of Hematology (2022)

Abstract Patients with B‐cell malignancies have suboptimal immune responses to SARS‐CoV‐2 vaccination and are a high‐risk population for severe COVID19 disease. We evaluated the effect of a third booster BNT162b2 vaccine on the kinetics of anti‐ SARS‐CoV‐2 neutralizing antibody (NAbs) titers in patients with B‐cell malignancies. Patients with NHL ( n = 54) Waldenström's macroglobulinemia ( n = 90) and chronic lymphocytic leukemia ( n = 49) enrolled in the ongoing NCT04743388 study and compared against matched healthy controls. All patient groups had significantly lower NAbs compared to controls at all time points. 1 month post the third dose (M1P3D) NAbs increased significantly compared to previous time points (median NAbs 77.9%, p &lt; .05 for all comparisons) in all patients. NAbs ≥ 50% were seen in 59.1% of patients, 34.5% of patients with suboptimal responses post‐second dose, elicited a protective NAb titer ≥50%. Active treatment, rituximab, and BTKi treatment were the most important prognostic factors for a poor NAb response at 1MP3D; only 25.8% of patients on active treatment had NAbs ≥ 50%. No significant between‐group differences were observed. Patients with B‐cell malignancies have inferior humoral responses against SARS‐CoV‐2 and booster dose enhances the NAb response in a proportion of these patients.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Current biomarkers for predicting the response to anti-PD-1 therapy require tissue biopsy and have not shown sufficient predictive values. Kim and colleagues discovered, in anti-PD-1-treated patients with metastatic or refractory thymic epithelial tumors and in patients with non-small cell lung cancer, a higher fold-change in the percentage of Ki-67+ cells among PD-1+CD8+ T cells 7 days after the first dose predicts superior durable clinical benefit and survival rates. This result was validated in an independent cohort of anti-PD-1-treated patients with non-small cell lung cancer. In summary, the first-week proliferative response of peripheral blood PD-1+CD8+ T cells predicts the response to anti-PD-1 therapy in solid tumors.CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are a new class of drugs that are approved alone or in combination with endocrine therapy for advanced estrogen receptor positive breast cancer. Clark and colleagues sought to combine palbociclib with paclitaxel using a novel dosing schedule taking advantage of the mechanism of action of both drugs to potentially increase the efficacy of single agent paclitaxel. Administering the drugs on an alternating schedule potentially enables G1-synchronization by palbociclib, a few days rest without drug allows cells to re-enter the cell cycle, increasing the percentage of cells in M phase when exposed to paclitaxel. Alternating sequential palbociclib/paclitaxel in patients with Rb+ ABC is feasible and safe, without evidence of additive toxicity.Nowicki and colleagues describe a clinical trial using dual cell immunotherapy, consisting of genetically modified lymphocytes with NY-ESO-1-specific T-cell receptor adoptively transferred together with NY-ESO-1 peptide-pulsed dendritic cell vaccination with or without CTLA-4 immune checkpoint blockade with ipilimumab. The authors report that these protocols are generally safe, feasible, and result in high antitumor activity in patients with advanced sarcoma and melanoma. However, further improvements in durability of these cellular therapies are needed because patients frequently relapse after an initially vigorous antitumor response.Cancer of the esophagus claims more than 400,000 lives annually year. Without efficient, reliable screening, diagnosis often occurs too late to save the patient. To this end, Wang and colleagues developed a minimally invasive, rapid test using a swallowable, retrievable sponge (EsophaCap) in conjunction with epigenetic biomarkers to detect precancerous changes (Barrett's esophagus) in cells lining the esophagus. The EsophaCap was administered to 94 people over the course of the study. The combination of p16, NELL1, AKAP12, and TAC1 methylation yielded high sensitivity and specificity in diagnosing Barrett's esophagus. These findings indicate the need for large prospective studies testing this early diagnostic modality.
Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: Past discoveries and future directions
Authors: Nicholas J. Short, Hagop Kantarjian
Journal: American Journal of Hematology (2022)

Azacitidine and decitabine are hypomethylating agents that have dose-dependent epigenetic and cytotoxic effects and are widely used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this review, we discuss the path to regulatory approval of azacitidine and decitabine, highlighting the substantial efforts that have been made to optimize the dosing schedule and administration of these drugs, including the development of new, oral formulations of both agents. We also review novel combination strategies that are being investigated in ongoing clinical trials for patients with MDS and AML, as well as efforts to expand the current indications of these agents.
How many steps to a feasible mouse model of hepatitis B virus infection?
Authors: Michael Nassal
Journal: Hepatology (2022)

1 Department of Internal Medicine 2/Molecular Biology University Hospital FreiburgFreiburgGermany *Correspondence Michael Nassal, Department of Internal Medicine 2/Molecular Biology, University Hospital Freiburg, Hugstetter Straße 55, D‐79106 Freiburg, Germany. Email: [email protected]
Suprachoroidal delivery enables targeting, localization and durability of small molecule suspensions
Authors: Viral S. Kansara, Shelley E. Hancock, Leroy W. Muya, Thomas A. Ciulla
Journal: Journal of Controlled Release (2022)

Drug delivery to the suprachoroidal space (SCS®) has become a clinical reality after the 2021 FDA approval of CLS-TA, a triamcinolone acetonide injectable suspension for suprachoroidal use (XIPERE®), administered via a microneedle-based device, the SCS Microinjector®. Suprachoroidal (SC) delivery facilitates targeting, compartmentalization, and durability of small molecule suspensions, thereby potentially addressing some of the efficacy, safety, and treatment burden limitations of current retinal therapies. Herein, the design features of the SCS Microinjector are reviewed, along with the biomechanics of SC drug delivery. Also presented are preclinical evaluations of SC small molecule suspensions from 4 different therapeutic classes (plasma kallikrein inhibitor, receptor tyrosine kinase inhibitor, corticosteroid, complement factor D inhibitor), highlighting their potential for durability, targeted compartmentalization, and acceptable safety profiles following microinjector-based SC delivery. The clinical evaluations of the safety, tolerability and efficacy of SC delivered triamcinolone further supports potential of SC small molecule suspensions as a clinically viable strategy for the treatment of chorioretinal diseases. Also highlighted are current limitations, key pharmacological considerations, and future opportunities to optimize the SC microinjector platform for safe, effective, and potentially long-acting drug delivery for the treatment of chorioretinal disorders.
Genetics and psychiatry
Authors: A Abdellaoui, K J H Verweij
Journal: American Journal of Psychiatry (1989)

For centuries, it has been suspected that the vulnerability to psychiatric problems might be heritable. In the 20th century, this was confirmed through twin and family studies, with heritability estimates ranging from ~30-40% for posttraumatic stress disorder and major depression to ~80 for schizophrenia and autism. In the 21st century, genome-wide association studies (GWASs) were introduced, a hypothesis-free design capable of locating DNA associations.<br /><br> AIM: To describe the development of genetic research in psychiatry.<br /><br> METHOD: Overview of selected literature.<br /><br> RESULTS: Increasingly larger GWASs show that the risk for psychiatric disorders is influenced by a combination of environmental factors and the sum of many genetic variants with small effects that combine to explain much variation. A substantial proportion of these genetic effects overlap between psychiatric disorders, but also with positive outcomes, such as IQ and educational attainment.<br /><br> CONCLUSION: We are experiencing a revolution in genetics, in which the sample size, and thus the predictive value of DNA, is growing faster than our understanding of the complexity of the inherited risk for psychiatric problems.<br>.
Closing the gap for drowning prevention across Europe
Authors: Amy E Peden, Jonathon Passmore, Ana Catarina Queiroga, Roger Sweeney, Jagnoor Jagnoor
Journal: The Lancet Public Health (2022)

Drowning is a preventable cause of premature mortality and was estimated to cause of 236 000 deaths globally in 2019.1 In WHO's European region, drowning was estimated to have resulted in the deaths of 19 444 people in 2019, a mortality rate of 2·1 per 100 000.1 This rate is lower than the global rate of 3·1 per 100 000 population, and the second lowest of any of the WHO regions, only higher than the rate of 1·8 per 100 000 in WHO's region of the Americas.
Redefining age-based screening and diagnostic guidelines: an opportunity for biological aging clocks in clinical medicine?
Authors: Jamaji C Nwanaji-Enwerem, William B Mair
Journal: The Lancet Healthy Longevity (2022)

Clinicians often note that patients seem older or younger than their stated age to convey their appraisal of a patient's biological or physiological age and subsequent disease risks. Developments in ageing biomarkers, such as epigenetic clocks,1 offer a more objective method of molecularly quantifying how well an individual is ageing beyond subject assessment. However, it remains unclear how best to incorporate these measures of so-called biological age into clinical medicine. Both a benefit and dilemma of incorporating epigenetic aging in clinical medicine is its association with a plethora of disease states while simultaneously being associated with various physical and psychosocial risk factors.
Factors associated with increased Emergency Department transfer in older long-term care residents: a systematic review
Authors: Carl Marincowitz, Louise Preston, Anna Cantrell, Michael Tonkins, Lisa Sabir, Suzanne Mason
Journal: The Lancet Healthy Longevity (2022)

The proportion of adults older than 65 years is rapidly increasing. Care home residents in this age group have disproportionate rates of transfer to the Emergency Department (ED) and around 40% of attendances might be avoidable. We did a systematic review to identify factors that predict ED transfer from care homes. Six electronic databases were searched. Observational studies that provided estimates of association between ED attendance and variables at a resident or care home level were included. 26 primary studies met the inclusion criteria. Seven common domains of factors assessed for association with ED transfer were identified and within these domains, male sex, age, presence of specific comorbidities, polypharmacy, rural location, and care home quality rating were associated with likelihood of ED transfer. The identification of these factors provides useful information for policy makers and researchers intending to either develop interventions to reduce hospitalisations or use adjusted rates of hospitalisation as a care home quality indicator.
Second-line therapy with nivolumab plus ipilimumab for older patients with oesophageal squamous cell cancer (RAMONA): a multicentre, open-label phase 2 trial
Authors: Matthias P Ebert, Nadja M Meindl-Beinker, Tobias Gutting, Martin Maenz, Johannes Betge, Nadine Schulte, Tianzuo Zhan, Philip Weidner, Elke Burgermeister, Ralf Hofheinz, Arndt Vogel, Stefan Angermeier, Claus Bolling, Maike de Wit, Ralf Jakobs, Meinolf Karthaus, Gertraud Stocker, Peter Thuss-Patience, Tobias Leidig, Timo Gaiser, Jakob N Kather, Nicolai Haertel
Journal: The Lancet Healthy Longevity (2022)

The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population.This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244.Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment.Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment.Bristol Myers Squibb.
Gut dysbiosis impairs hippocampal plasticity and behaviors by remodeling serum metabolome
Authors: Guoqiang Liu, Quntao Yu, Bo Tan, Xiao Ke, Chen Zhang, Hao Li, Tongmei Zhang, Youming Lu
Journal: Gut Microbes (2022)

Accumulating evidence suggests that gut microbiota as a critical mediator of gut-brain axis plays an important role in human health. Altered gut microbial profiles have been implicated in increasing the vulnerability of psychiatric disorders, such as autism, depression, and schizophrenia. However, the cellular and molecular mechanisms underlying the association remain unknown. Here, we modified the gut microbiome with antibiotics in newborn mice, and found that gut microbial alteration induced behavioral impairment by decreasing adult neurogenesis and long-term potentiation of synaptic transmission, and altering the gene expression profile in hippocampus. Reconstitution with normal gut flora produced therapeutic effects against both adult neurogenesis and behavioral deficits in the dysbiosis mice. Furthermore, our results show that circulating metabolites changes mediate the effect of gut dysbiosis on hippocampal plasticity and behavior outcomes. Elevating the serum 4-methylphenol, a small aromatic metabolite produced by gut bacteria, was found to induce autism spectrum disorder (ASD)-like behavior impairment and hippocampal dysfunction. Together our finding demonstrates that early-life gut dysbiosis and its correlated metabolites change contribute to hippocampal dysfunction and behavior impairment, hence highlight the potential microbiome-mediated therapies for treating psychiatric disorders.
Development of a highly efficient prime editor 2 system in plants
Authors: Juan Li, Like Chen, Jing Liang, Rongfang Xu, Yingli Jiang, Yizhen Li, Jian Ding, Min Li, Ruiying Qin, Pengcheng Wei
Journal: Genome biology (2022)

Abstract Low efficiency has seriously restricted the application of prime editing (PE) systems in plants. In this study, we develop an enhanced plant prime editor 2 system, enpPE2, by stacking various optimization strategies, including updating the PE architecture to PEmax and expressing engineered pegRNA with a structured motif under the control of a composite promoter. In T 0 rice plants, enpPE2 exhibits editing frequencies of 64.58% to 77.08%, which are much higher than the frequencies with unmodified pPE2. Our results indicate that the enpPE2 system provides a robust and powerful tool for the precise modification of plant genomes.
ZetaSuite: computational analysis of two-dimensional high-throughput data from multi-target screens and single-cell transcriptomics
Authors: Yajing Hao, Shuyang Zhang, Changwei Shao, Junhui Li, Guofeng Zhao, Dong-Er Zhang, Xiang-Dong Fu
Journal: Genome biology (2022)

Abstract Two-dimensional high-throughput data have become increasingly common in functional genomics studies, which raises new challenges in data analysis. Here, we introduce a new statistic called Zeta, initially developed to identify global splicing regulators from a two-dimensional RNAi screen, a high-throughput screen coupled with high-throughput functional readouts, and ZetaSuite, a software package to facilitate general application of the Zeta statistics. We compare our approach with existing methods using multiple benchmarked datasets and then demonstrate the broad utility of ZetaSuite in processing public data from large-scale cancer dependency screens and single-cell transcriptomics studies to elucidate novel biological insights.